Derivatives of thiopyranothiazoles



DERIVATIVES OF THIOPYRANOTHIAZOLES :Robert H. Sprague, Shaker Heights, Ohio, assignor to Horizons Incorporated, Cleveland, Ohio, a corporation of New Jersey No Drawing. Filed Sept. 29, 1958, Ser. No. 7 63,7 86

Claims. (Cl. 260-302) This invention relates to a new class of chemical compounds useful as accelerators for the vulcanization of rubber, as fungicides or insecticides and as pharmaceuticals, including utility-as analgetics, antitubercular drugs and tranquilizers. More specifically it relates to a new thiazole: 6,7-dihydro-4-H-thiopyrano(4,3d)thiazole and to a series of derivatives thereof which are particularly useful as accelerators for the vulcanization of rubber and which may also be useful as pharmaceuticals.

A vast amount of research has been reported on the vulcanization of rubber and rubber-like materials. Among the classes of compounds which are described in the literature arethose based on thiazole derivatives such as Z-mercaptobenzothiazole or Z-mercaptotetrahydrobenzothiazole or Z-aminobenzothiazole; or sulfenamides and sulfenimides derived from the mercaptothiazoles and aminothiazoles respectively. It has also been reported that the partially reduced analogues of the above materials such as the tetrahydrobenothiazole derivatives are useful for these purposes.

Otherrelated compounds such as the thiazoline-Z-ones have recently been described as useful as. analgetics. Still other related compounds, namely the thiazolines or oxazolines have been suggested as antitubercular drugs.

I have now found that the introduction of a substituent ticularly the introduction of sulfur in place of one of the carbons, results in compounds having improved utility as vulcanization accelerators, or insecticides or fungicides, or as pharmaceuticals of the types indicated.

' into the saturated ring fused to the thiazole ring and par- Specifically, one aspect of the present invention concerns a new thiazole ring system derived from tetrahydro- 1-thio-4-pyrone and new compounds containing this new ring system.

The following examples are intended to be illustrative of the present invention and are by no means exhaustive of the useful derivatives obtainable within the intended scope of the invention.

Example 1.-3-bromo-l-thiotetrahydro-4-pyrone (prepared by the method of R. H. Sprague, I. Am. Chem. Soc.,

79, 2281 (1957)) may be condensed with ammonium dithiocarbamate by refluxing the mixture inethersolution, givingIZ- ercapto-6,7-dihydro-4 H-thiopyrano(4,3d)thiazole.

one I /Cg /s on, .o'=os 0 +NH2CSSNHA'") 1 H CSH s CHBr H2 0 CH; C 2 1 Example 2.A mixture of the mercaptothiazole prepared by the method of Example 1 with cyclohexylamine and aqueous sodium hydroxide solution may be oxidized with a solution of iodine in potassium iodide, giving N cyclohexyl-(6,7-dihydro-4-H thiopyrano(4,3d)thiazolyl- 2) sulfenamide.

tide, sodiumm-butylmercaptide; sodium cyclohexyl mer I 2,940,979 Patented J une 14,1960

ice

/CE: NH ./0 Hi s on, o=o t s c mo. l (l) +CS JJ ON'H2-- s HBr E, C\/

on, 3 cm Br- /CE: /S a s o 4 CNH:

t CH3 Example 4 .--The- 2-amino-6,7-dihydro-4-H-thiopyrano (4,3d) thiazole may be alkylated by methyl iodide in alcohol solution in the presence of alkali, giving 3-methyl-2- im1nm6,7edihydro-4-Hethiopyrano(4,3d)thiazoline; 1

The methyl iodide in the above reaction may be replaced by a variety of alkylating agents-such as ethyliodide, ethylsulfate, butylbromide, 'be'n'zyl bromide, yieldingthe corresponding Na1kylthiazoline derivative. t

"Example 5 .--The 3 methyl '-2-imino-6,7-dihydro-4.-H- thiopyrano(4,3d)thiazoline may also be prepared by condensing 3-thiocyano-l-thiotetrahydro-4-pyrone (prepared from the bromo ketone and barium thiocyanate, using theprocedure of de Stevens, et al., J. Am. Chem. Soc., 79, 5263 (1957)) with methylamine in alcohol solution. The product is identical with that obtained in Example 4.

Example 6.The iminothiazole produced by the methods of Examples 4 or 5 may also be chlorinated with NaOCl in cold Na CO solution to 2-chloro-imino-3- methyl-6,7-dihydro-4-H-thiopyrano(4,3d)thiazoline.

en, s

CH: The chloroimino compound thus obtained may be reacted with mercaptides-such as sodium phenylmercapcaptide, fe'tc.-.to l-give sulfenimides useful as vulcanization accelei'ators." For example, addition of a cold solufiOllOf NaQCI inwa'ter to a stirred mixture of Si-methyl 2 imino GJ-dihydro 4 H-thiopyrano(4,3d) thiazoline and an alkaline solution-of cyclohexylmercaptan, followed by heating'rapidly to C. gives cyclohexyl-(B -methylsulfenimide. U

f on on S 1- a 1 I C=NSCH V 7 0H,

\ CHE-C a i ii 7 1 ineman Eqran pie 7.-'-The 2-me rcapto-6,7-dihydro-4 H-thio- V 1 pyrano (4,3d)thiazole prepared as inExample 1 may be oxidized in aqueous sodium hydroxide solution with chlomine to give 4 2,2'-dithiorbis(ejl-dihydroA-H-thio- Example '8..Chlorinating1 the product of Example '1 in acetic acid solution produces V2!ch1oro.- 67 +dihydro-.4;-

H -thiopyrano(4,3d)-thiazole which may. be condensed with sodium dimethyldithioearbamate in aqueous sodium hydroxide, giving dimethyldithiocarbamyl-Z-(oJ-dihydro-.

4- I-I,-thiopyrano(4,3d) thia zolyl) sulphide.

1; mpze1b; ;3 somenhiotmrydmasme m be condensedzwith ,ethylzxanthamidatein ethyl alcohol solutionggiving. 6; -dihydro-r4r-,H-vthiopyrano(4,3d)thiezo Exom ple 11, 'Ifh e product of Example 10 may be alkylated with methyl iodide, .giving 3-methy1-6,'7-dihydro- 4-H-thiopyrano(4,3d)thiazolin 2Fone.

7 .GH: S

fing the corresponding N-substituted compounds.

gnawnpzg 12.+-3-hromo1-thiotetrahyd11oi4-pyroneQmay "he ieondensed with diphenyl thioureaiby refluxing the V components in absolute ethanol for 6 hours, giving 3.-

' '(4,3d) thiazoline. 7

CH2 S v Diethylthiourea, dicyclohexylthiourea, and other substitutedthiou'reas may be employed in place of the'diphenylthiourea given by way of example to produce the corresponding thiazoline derivatives.

'The foregoing examples illustrate the several classes of u u wmpounsls ri hma b p repa i r -r mm a F thiaiole'ring system. The following examples lists'e'veral methods of prefiarin'g substituted haloketonejs, leading to substituted versions of the new thiazole described above.

10 Example 13.3-bromo-1-thiotetrahydro 4 pyronemay be reacted with secondary amines such as .diethylamine,

nfor example, giving 3-diethylamino-1-thiotetrahydro-4- pyrone. This maythen' be'bromin'ated, giving a haloketone which may be used in any of the above syntheses to prepare new thiazole derivatives. The seqlience of reactions is outlined below: i r

n dial-kylamines, piperidine, morpholine; -pyrrolidine, etc. I

Example 14.'-The M'annich reaetion may-be' employed V with tetrahydro I thioA-py'mne;for the preparationvo f new thiazole derivatives as-outlined =be1oW: 5i

Example 15 .--Compounds similar to the products from Example 14, but having a lengthened gp olymethylene chain joining the secondary amino groupto the hemthiazoline ring at position 4, may be prepared by the following series of reactions:

1. A thiazole having the general formula selected from wherein R is a monovalent radical selected from the group consisting of hydrogen, diethylamino, B-dimethylaminoethyl, and piperidinomethyl; R is a monovalent radical selected from the group consisting of hydrogen,

5 methyl, ethyl, propyl, butyl, cyclohexyl, benzyl and phenyl; X is a member selected from the group consisting of hydrogen, chlorine, phenylmercapto, n-butylmercapto, cyclohexylmercapto, cyclohexyl, and phenyl; and Y is a member selected from the group consisting of 2. The compound 2-mercapto-6,7-dihydro-4-H-thiopyrano(4, 3d) thiazole.

3. The compound 3 methyl-Z-imino-6,7-dihydro-4-H- thiopyrano (4, 3d) thiazoline:

f3 s (3 (?=NH 31H: /C-III CH1 CHI 4. The compound S on CH 1 l I! C=NS-CH CH: on o 35 1? 2- 2 0H,

5. The compound )5 l Cfin \III CH;

References Cited in the file of this patent Erlenmeyer et al.: Chem. Abstracts, vol. 42, col. 4165 (1948). 

1. A THIAZOLE HAVING THE GENERAL FORMULA SELECTED FROM THE GROUP CONSISTING OF: 